Patient-Reported Outcome Measures in Patients with Thrombotic Thrombocytopenic Purpura: A Systematic Review of the Literature

Health-related quality of life (HRQoL) impacts of thrombotic thrombocytopenic purpura (TTP) have been captured in clinical studies using patient-reported outcome (PRO) measures (PROMs) that are validated for other diseases. However, the validity evidence to support the use of existing PROMs in patients with TTP is unknown. In a systematic review of the literature, including studies of adults and children with TTP, we assessed the validity evidence for use of PROMs in clinical research and clinical practice, characterized HRQoL, described the integration of PROMs in clinical practice and evaluated PRO scores for patients with TTP compared with reference populations. From an initial 4518 studies, we identified 14 studies using 16 PROMs to assess general HRQoL domains in patients in remission. No identified studies assessed the validity of PROMs for the context of use of TTP and no studies described PROM integration into TTP clinical practice or evaluated PROMs that were specific for patients with TTP. Moreover, PRO scores were worse in patients with TTP compared with reference populations and other chronic conditions. We conclude that, in patients with TTP, PROMs pick up on important patient experiences not captured by clinical outcomes at present. There is, therefore, a need for studies that assess the validity of existing PROMs in patients with TTP to determine if TTP-specific PROMs specific to patients with TTP should be developed.

HRQoL impacts are best measured using patient reported outcome measures (PROMs). PROMs are self-completed tools that assess one or multiple outcomes from the patient's perspective. PROMs capture HRQoL impacts by direct patient self-report, without interpretation through the lens of a healthcare provider [10]. PROMs can help assess disease burden and evaluate response to therapy [11][12][13]. PROMs can also help improve the assessment of HRQoL impacts of therapies by patients, clinicians, and researchers. Additionally, if shown to be valid and reliable, PROMs can be used to support FDA approval of candidate therapies in clinical trials [14].
PROMs are increasingly being used in research studies to measure TTP-associated HRQoL impacts. However, it is not known if and how PROMs have been implemented in TTP clinical settings. It is also not known whether PROMs used at present capture TTP-specific HRQoL impacts or how they may change TTP clinical management. Finally, it is also not known what the validity evidence is for using PROMs for the context of use of TTP. Therefore, to define the landscape of PROMs at present and their validity evidence in studies of patients with TTP, we undertook a systematic review of the literature. As an exploratory objective to characterize TTP-related morbidity, we also reported patientreported outcomes (PROs) scores across studies.

Search Strategy and Selection Criteria
This study was a systematic review reported in concordance with PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [15], and registered with PROSPERO (Registration CRD42022347498) [16].
An electronic search of the literature was conducted using the databases Medline (PubMed), Embase (Elsevier), Scopus (Elsevier), and CINAHL (EBSCO) from inception to 10 June 2022. On 10 October 2022, an updated and more sensitive search was completed, to which was added ClinicalTrials.gov. Search keywords were the following: thrombotic thrombocytopenic purpura, quality of life, anxiety, memory, cognition, outcome, attention, and PROMs (for the detailed search strategy, see supplemental Appendix SA Table SA1-SA9).
Study inclusion criteria were the following: (1) studies of patients with a TTP clinical diagnosis (regardless of ADAMTS13 activity) and (2) studies that reported on the use of PROMs (utilization, development, and testing of measurement properties). PROMs could include known PROMs previously identified in the literature or any other patient self-administered instrument.
Studies were excluded for the following reasons: (1) the population included patients with hereditary TTP alone; (2) PROMs were not evaluated; or (3) PRO results were not reported. Also excluded were case reports (sample size of one patient), reviews, commentaries, studies in non-human subjects, and studies in languages other than English.
The search strategy included a manual review of published article reference lists. We also searched were unpublished studies using gray literature sources (ClinicalTrials.gov and Embase). References were compiled in Endnote and articles were uploaded into Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia) [17]. After deduplication, all titles and abstracts were screened by two independent reviewers (ASFJ and MPML) to determine their suitability for a full-text review. Full-text articles were reviewed by the same independent reviewers (ASFJ and MPML). Conflicts were resolved through a discussion between the two reviewers or by a binding vote from a third independent reviewer (OAO).

Data Analysis
Study quality was assessed by two independent reviewers (ASFJ and MPML) using the Joanna Briggs Institute Clinical Appraisal Tools checklist for Cross-Sectional, Cohort, and Clinical Trial Studies [18]. Conflicts were resolved through discussions or by a third independent reviewer (OAO).
As an initial template to capture the data, the reviewers used a data abstraction table. Summary data were extracted from published reports and included the following variables: primary author and year of study; study objective; number of patients; time from last TTP episode; mean time of PROM completion; PROM characteristics (names, number of PROMs used, and domains assessed); PROM clinical practice integration strategies; PROM clinical practice integration impacts; and PRO scores for patients with TTP and the reference population.
As an exploratory objective to characterize TTP-related morbidity across studies, PRO scores comparing patients with TTP to normal controls or the general population were reported. This report assumed that the PROMs were appropriate for patients with TTP within the specified contexts of use. Where applicable, the results of statistical analyses performed within each study are noted.
Finally, in a post hoc analysis, we identified important TTP domains from the patient's perspective that have not yet been assessed by studies evaluating PROMs in the literature.

Included Studies
Following deduplication, the search strategy yielded 4518 studies for screening. Nine additional articles were identified through article reference lists. After the abstract review, 41 articles advanced to a full-text review. Of those 41 articles, 25 studies were excluded (see Figure 1). Studies excluded for using instruments that did not meet criteria for PROMs are summarized in Table S1 (Supplementary Materials) [7, 13,[19][20][21][22][23][24][25][26][27]. Therefore, 16 articles were advanced to a quality review. During the quality review, two additional studies were excluded due to the inability to distinguish the results of patients with TTP from those of other diseases [28,29]. Therefore, the final number of studies for analysis was 14, of which five (36%) were cross-sectional studies, eight (57%) were cohort, and one was a clinical trial (7%). These 14 studies covered 16 PROMs in 970 patients with TTP. Study quality was assessed by two independent reviewers (ASFJ and MPML) using the Joanna Briggs Institute Clinical Appraisal Tools checklist for Cross-Sectional, Cohort, and Clinical Trial Studies [18]. Conflicts were resolved through discussions or by a third independent reviewer (OAO).
As an initial template to capture the data, the reviewers used a data abstraction table. Summary data were extracted from published reports and included the following variables: primary author and year of study; study objective; number of patients; time from last TTP episode; mean time of PROM completion; PROM characteristics (names, number of PROMs used, and domains assessed); PROM clinical practice integration strategies; PROM clinical practice integration impacts; and PRO scores for patients with TTP and the reference population.
As an exploratory objective to characterize TTP-related morbidity across studies, PRO scores comparing patients with TTP to normal controls or the general population were reported. This report assumed that the PROMs were appropriate for patients with TTP within the specified contexts of use. Where applicable, the results of statistical analyses performed within each study are noted.
Finally, in a post hoc analysis, we identified important TTP domains from the patient's perspective that have not yet been assessed by studies evaluating PROMs in the literature.

Included Studies
Following deduplication, the search strategy yielded 4518 studies for screening. Nine additional articles were identified through article reference lists. After the abstract review, 41 articles advanced to a full-text review. Of those 41 articles, 25 studies were excluded (see Figure 1). Studies excluded for using instruments that did not meet criteria for PROMs are summarized in Table S1 (Supplementary Materials) [7, 13,[19][20][21][22][23][24][25][26][27]. Therefore, 16 articles were advanced to a quality review. During the quality review, two additional studies were excluded due to the inability to distinguish the results of patients with TTP from those of other diseases [28,29]. Therefore, the final number of studies for analysis was 14, of which five (36%) were cross-sectional studies, eight (57%) were cohort, and one was a clinical trial (7%). These 14 studies covered 16 PROMs in 970 patients with TTP.

PROMs in Unpublished Studies
Three studies were identified through clinicaltrials.gov and the published results were available for one study: the post-HERCULES trial (included in summaries of published studies above). Published results were not available for two studies: the ConNeCT Study (Neurological Complications of TTP), an observational study, and CAPLAVIE (Efficacy of a Personalized Caplacizumab Regimen Based on ADAMTS13 Activity Monitoring in Adult TTP), a clinical trial [26,27]. While the ConNeCT study assessed depression and overall HRQoL using PHQ-9 and SF-36 [26], the CAPLAVIE trial assessed PTSD

PROMs in Unpublished Studies
Three studies were identified through clinicaltrials.gov and the published results were available for one study: the post-HERCULES trial (included in summaries of published studies above). Published results were not available for two studies: the ConNeCT Study (Neurological Complications of TTP), an observational study, and CAPLAVIE (Efficacy of a Personalized Caplacizumab Regimen Based on ADAMTS13 Activity Monitoring in Adult TTP), a clinical trial [26,27]. While the ConNeCT study assessed depression and overall HRQoL using PHQ-9 and SF-36 [26], the CAPLAVIE trial assessed PTSD symptom severity using the PCL-5 [27].

PROMs Capturing the Impact of TTP-Related Morbidity
The results of our exploratory analyses, in which HRQoL domains in patients with TTP were compared with a reference population, are shown in Supplementary Tables S2-S4. In general, following recovery from an acute TTP episode, patients had significant HRQoL impacts.
When PROMs were used to assess overall HRQoL, patients with TTP had worse scores than the general US and Italian population (norms). Additionally, patients with TTP had similar or worse scores than patients with other chronic conditions (anemia, cancer, and depression) [2,5,8,13,19,20,58,66].
Similar findings are shown when PROMs are used to assess specific HRQoL domains. Across the studies, there was a statistically higher prevalence of depression and anxiety in patients with TTP when compared with the control groups [4,7,9,58]. Additionally, in patients with TTP, a positive PTSD screen was prevalent (35%) [52]. Patients with TTP also had worse scores than healthy controls in cognitive function (memory, attention, executive function, and cognitive function abilities) [5,9]. Finally, patients with TTP reported significant impacts on work-related quality of life (see Supplementary Tables S2-S4) [5].
Most studies (5/7, 71%) assessed the relationship between TTP episode characteristics and depression and anxiety. In these studies, anxiety and depression were assessed after the TTP episode; however, the time from the TTP episode to administering the PROM was reported by only two studies [7,52]. For these studies, the median time from the TTP episode to administering the PROM was 6.3 and 6.6 years. Depression and anxiety scores were not statistically associated with number of TTP episodes [4,7,9,52], presence of neurological symptoms [4,9,52], number of TPE procedures [4], ADAMTS13 activity during remission [7], and abnormal MRI [21].
One study assessed the relationship between TTP episode characteristics and scores on all SF-36 domains after the initial TTP diagnosis (median time 1.53 years). Scores on all domains were not statistically associated with TTP clinical triggers (idiopathic vs. other), presence of severe ADAMTS13 deficiency, number of TPE procedures, and presence of neurologic symptoms [2].
Additionally, one study assessed the relationship between TTP episode characteristics and HIT-6 scores after the last TTP episode (average time: 3.12 years). Although no statistical analyses were performed, the study suggested that headache severity scores were not associated with the number of TTP episodes, time from last TTP episode, or ADAMTS13 activity level [8].
Finally, one study assessed the relationship between TTP episode characteristics and cognitive deficits using FLei. Cognitive scores were not found to be statistically associated with the number of TTP episodes and the presence of neurological symptoms [9].

Discussion
Our systematic review identified 14 studies that used 16 PROMs to assess HRQoL domains in TTP. The five main findings were the following: (1) the small number of studies using PROMs in patients with TTP; (2) the absence of studies assessing psychometric properties of PROMs in patients with TTP; (3) the absence of studies evaluating strategies for, and the impact of, integrating PROMs into TTP clinical practice; (4) the absence of PROMs developed specifically for patients with TTP; and (5) decreased HRQoL in patients with TTP when compared with reference populations and other chronic conditions. PROMs were originally developed for pharmacological research to assess therapeutic effectiveness [71]. More recently, PROMs have been used to support clinical decision making, prioritize patients for surgical procedures, and improve healthcare quality in clinical practice [71,72]. When integrated into clinical practice, PROMs have been shown to optimize provision of patient-centered healthcare, reduce healthcare services utilization, and enhance patient-clinician communication. PROMs have also been shown to increase patient satisfaction and improve HRQoL outcomes [73,74]. In the clinical care of patients with chronic conditions, PROMs have been shown to both improve disease activity and increase survival [73].
Although PROMs are used in hematological research, little is known about their integration into hematology clinical practice [68,75]. For chronic hematological disorders, integrating PROMs into clinical practice may reduce disease burden through the early identification and management of residual symptoms, such as fatigue, depression and anxiety [68,75]. Despite the growing number of PROMs being applied in hematology, integrating PROMs into clinical practice poses some challenges. First, a standard PROM scoring system does not exist and medical providers find it difficult to make clinical decisions using normative-based scores [76]. Second, the integration of PROMs into healthcare systems may be influenced by structural barriers. These barriers include consultation time, absence of implementation recommendations, and prioritization of laboratory outcomes [75]. Third, successful integration relies on using validated PROMs that have undergone psychometric processes to ensure that the PROM measures what is intended [75]. Although PROMs represent the patient's views of their own health, the outcome assessed may not be important to the patient or to health itself [71]. Therefore, PROMs that are ideal for use in clinical practices are those that both assess important outcomes for patients and providers and are valid, reliable, and specific to the context of use for the disease under study [71].
In other chronic conditions with significant impacts on HRQoL, PROMs have been used for clinical purposes [12,[77][78][79]. In two prior systematic reviews, PROMs were identified to have the potential to be applied to clinical practice in the following five ways: (1) assess HRQoL in a structured and validated way; (2) foster patient-clinician communication; (3) monitor therapeutic impacts on HRQoL; (4) develop personalized management plans; and (5) increase health awareness [12,77]. Similar clinical applications were also suggested by a qualitative study of 44 patients with TTP in remission. In this study, focus groups (7 groups; n = 25) and individual interviews (n = 19) were conducted to assess TTP residual symptoms and patient-hematologist communication [68]. In all 7 (100%) focus groups and 18 (95%) individual interviews, patients reported residual TTP symptoms that were negatively impacting their activities of daily living [68]. Most patients also reported barriers to communicating these residual symptoms to their hematologists. Based on the abovementioned studies and considering TTP-related morbidity, the potential goals for PROM utilization in TTP are summarized in Figure 3.
Despite these potential applications in TTP care, integrating PROMs into clinical practice poses the aforementioned challenges [75,76]. Therefore, future prospective studies are desired to determine the optimal strategies for integrating PROMs into TTP clinical practice and assess other potential applications.
Our post hoc analysis revealed TTP domains that were felt to be important from the patient's perspective but were not evaluated in any of the included studies (see Figure 2). In a qualitative study of 50 patients, Holmes et al. identified domains that were important to patients with TTP. These domains included: (1) fatigue; (2) cognitive domains of attention, concentration, and the ability to use language; (3) ability to travel; (4) fear of relapse; and (5) desire/ability to have sex [5]. Another qualitative study of 44 patients with TTP determined that the most important symptoms impacting activities of daily life were cognitive impairment, fatigue, relapse-related anxiety, and depression [68]. Another study by Oladapo et al. reported that domains previously identified as important to patients with hereditary TTP were also relevant to patients with acquired TTP. These domains included vision problems, bruising, dizziness, numbness, sleep disturbance, and fear of relapse [69,70]. Although these domains may be assessed by PROMs available at present, these PROMs cannot be recommended for use in patients with TTP until studies are conducted to evaluate the content validity (understandability and appropriateness) for the context of use of TTP [80]. Thus, content validity studies are needed to facilitate the interpretation of currently available generic PROMs in patients with TTP. tion; (3) monitor therapeutic impacts on HRQoL; (4) develop personalized management plans; and (5) increase health awareness [12,77]. Similar clinical applications were also suggested by a qualitative study of 44 patients with TTP in remission. In this study, focus groups (7 groups; n = 25) and individual interviews (n = 19) were conducted to assess TTP residual symptoms and patient-hematologist communication [68]. In all 7 (100%) focus groups and 18 (95%) individual interviews, patients reported residual TTP symptoms that were negatively impacting their activities of daily living [68]. Most patients also reported barriers to communicating these residual symptoms to their hematologists. Based on the abovementioned studies and considering TTP-related morbidity, the potential goals for PROM utilization in TTP are summarized in Figure 3.  There may be a potential benefit of incorporating PROMs that assess specific domains relevant to patients with TTP [5,[68][69][70]. Disease-specific PROMs are designed to capture elements relevant to a specific population or condition and can be used to identify unmet needs and patients priorities [81][82][83]. Rather than disease-specific PROMs, TTP studies have used only generic PROMs. Although widely used across different diseases, generic PROMs may not be sensitive enough to pick up certain specific aspects of the disease under study [81]. Therefore, including disease-specific PROMs in clinical studies would illuminate important information about the impacts of TTP and TTP therapies from the patient's perspective [5,69,70]. Nevertheless, to guide the development of TTP-specific PROMs, future studies are needed using validated methodological processes. These would include both quantitative and qualitative studies [84].
The strengths of our study lie in its comprehensive review of the landscape of PROMs used in patients with TTP and summary of TTP-related morbidity based on PRO scores. Our review, however, is limited by the overlap of patients across studies, in which PROMs may have been repeatedly administered to the same population. Additionally, since ADAMTS13 activity was not used as an inclusion criterion, patients with other types of thrombotic microangiopathy may have been included among our cohort. Furthermore, since our review included qualitative studies only in a post hoc analysis, some concepts, such as understandability, could not be assessed. Finally, the heterogeneity in domains assessed by different PROMs prevented effective comparisons across studies. Nevertheless, our systematic review is an important milestone in defining the landscape of PROMs in TTP and providing data to guide future studies assessing the use of PROMs in patients with TTP.

Conclusions
Although PROMs are being used to assess several domains in patients with TTP, studies assessing the psychometric properties of present measures are desired. Additionally desired are qualitative concept elicitation studies. These studies would assess the acceptability of current PROMs for the context of use of patients with TTP. They would also determine whether existing PROMs should be modified for use in patients with TTP or whether there is a need to develop disease-specific PROMs.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/jcm12155155/s1, Appendix SA: Detailed search strategy (Tables SA1-SA9). Table S1: List of instruments excluded in the full-text review; Table S2: patientreported outcome measures in patients with TTP assessing physical health; Table S3: patient-reported outcome measures in patients with TTP assessing mental health and cognitive function; Table S4: patient-reported outcome measures in patients with TTP assessing work productivity.